The candidate is a neurologist/psychiatrist with training in neurobiology, and an assistant professorof psychiatry and neurology at the Washington University School of Medicine (WUStL),a world leading institution in genetics and epidemiology ofpsychiatric disorders. The candidate's immediate goal is to complete a master's degree in epidemiology and genetics to maximizeopportunities afforded by his currently funded research and under the mentorship of Dr. Cloningerand Dr. Goate. His long term goal is to concentrate his research career on the study ofthe genetic control ofthe relationship between parkinsonism and schizophrenia. Project. Parkinsonism is highly prevalent in newlydiagnosed -untreated- patients with schizophrenia; its presence predicts greater susceptibility to neuroleptic-induced side effects, reduced treatment compliance and poorer outcome. Smokinghas a negative association with parkinsonism, whereas hyperechogenicity of the substantia nigra, executive function and working memory deficits, and increased harm avoidance on the temperament and character inventory are all positively associated with motor impairment. These diverse phenotypic manifestations are related to a single neurobiological mechanism, namely decreased dopaminergic function. Studyinguntreated patients prevents the noise introduced into such phenotypic manifestationsby the effects of antipsychotic drugs, and therefore will permit isolation of the genetic signal from environmental noise (represented by treatment). We identified a population with untreated schizophrenia, and collected a pilot sample to study the clinical, neuropsychological and neurological characteristics ofpatients, their first degree relatives, and culturally appropriate controls. We propose to expand the sample. With the funds ofthis award we will focus on the clinical characterization of the probands and their siblings as well as of controls and their siblings to investigate the heritability ofa composite endophenotype including parkinsonism, smoking, cognitive deficit and hyperechogenicity of the substantia nigra. Towards the end of the award period we will work on an Roi application to study the relationship of the proposed phenotype to quantitative trait loci (QTL). The major relevance of the proposed research lies on the possibility of testis if a neurobiologicallywell defined set ofindividual characteristics is genetically determined. Because these deficitspossibly predate the onset of psychosis, we believe our strategy might provide tools for early detection and early intervention, possibly leading to prevention of psychosis in subjects at-risk for schizophrenia. Lastly, we anticipate that our research strategy may indicate new waysto study and address the increased vulnerability of schizophrenic patients to nicotine dependence.